Project Summary/Abstract The goal of this study is to conduct a two-site, double-masked, randomized, non-inferiority clinical trial through an experimental therapeutics approach to develop magnetic seizure therapy (MST) as a useful and safe treatment for treatment resistant depression (TRD). In this study, we propose to compare the efficacy of MST to right unilateral ultrabrief pulse electroconvulsive therapy (RUL-UB-ECT) in regards to suicidal ideation, depressive symptoms, and cognitive adverse effects in 260 patients with TRD. Importantly, for these two convulsive therapies, we will identify the neurophysiological targets corresponding with suicidal ideation reduction and cognitive adverse effects. ECT is a well-established treatment for TRD, but in Canada and the United States, less than 1% of patients with TRD receive ECT mainly due to its cognitive adverse effects (i.e., amnesia). Thus, new treatment alternatives for TRD are urgently needed. One such treatment is MST. MST involves applying a train of high frequency magnetic stimuli to induce a seizure (compared with ECT that involves applying a train of high frequency electrical stimuli to induce a seizure). Our pilot data demonstrated that MST can achieve efficacy that is comparable to ECT but with negligible cognitive adverse effects. Understanding the neurobiology of TRD, with an emphasis on suicidal ideation, can help accelerate treatment development. In this proposal, we will evaluate the rates of remission of suicidal ideation of MST compared to ECT and evaluate whether change in CI from the dorsolateral prefrontal cortex using combined transcranial magnetic stimulation and electroencephalography is associated with remission of suicidal ideation. We will also determine the cognitive adverse effects and their neurophysiological targets following a course of ECT in patients with TRD through electroencephalography. Positive results from this trial may have tremendous and immediate impact for patients with TRD. First, if MST demonstrates comparable treatment efficacy to ECT, but with fewer neurocognitive side effects, it could rapidly be adopted into clinical practice. Indeed, given that the administration of MST is nearly identical to ECT, all ECT facilities in North America would be able to readily adopt MST. Second, the absence of neurocognitive side effects will also lead to improved treatment acceptability. Lastly, by investigating key neurophysiological mechanisms of these treatments, we hope to derive critical mechanistic information underlying TRD treatment.